.alpha.,.alpha.-Disubstituted-.alpha.-hydroxy acetic acids are starting materials and intermediates for manufacturing compounds that have important biological and therapeutic activities. Such compounds include, for example, oxybutynin, oxyphencyclimine, oxyphenonium bromide, oxypyrronium bromide, and oxysonium iodide, for which cyclohexylphenylglycolic acid (CHPGA) is of special interest.
Racemic CHPGA is generally prepared by one of two methods: (1) selective hydrogenation of phenyl mandelic acid or of phenyl mandelate esters, as shown in Scheme 1; or (2) cyclohexyl magnesium halide addition to phenylglyoxylate as shown in Scheme 2. ##STR2## R is hydrogen or lower alkyl. ##STR3##
The synthesis of individual enantiomers of CHPGA has been approached along the lines of Scheme 2, by Grignard addition to a chiral auxiliary ester of glyoxylic acid to give a diastereomeric mixture of esters. In general, simple primary alkyl or phenyl Grignard (or alkyllithium) reagents were used for the addition, and the addition of inorganic salts (e.g. ZnCl.sub.2) sometimes appeared to increase the diastereoselectivity of the products. As outlined in Scheme 3, the simple chiral ester wherein R* is the residue of a chiral alcohol, can be hydrolyzed to yield chiral CHPGA (R'=H), or directly converted to chiral drugs or drug candidates by trans-esterification (R'=acetate), for example by reaction with an amino alcohol side chain to prepare S-oxybutynin. ##STR4## While these methods are adequate for many purposes, the chemical yields are in some cases poor, and the stereoselectivity is not always high. The chiral auxiliary reagents that give good yields and higher stereoselectivity are often quite expensive. There remains therefore a need for a highly stereoselective synthesis of CHPGA and related compounds that provides high chemical yields at lower cost.